Elsevier eBooks, Journal Year: 2022, Volume and Issue: unknown, P. 843 - 868
Published: Sept. 16, 2022
Language: Английский
Cell Reports, Journal Year: 2023, Volume and Issue: 42(3), P. 112284 - 112284
Published: March 1, 2023
B cells generate functionally different classes of antibodies through class-switch recombination (CSR), which requires classical non-homologous end joining (C-NHEJ) to join the DNA breaks at donor and acceptor switch (S) regions. We show that RNA-binding protein HNRNPU promotes C-NHEJ-mediated S-S 53BP1-shieldin DNA-repair complex. Notably, binds S region RNA/DNA G-quadruplexes, contributing regulating R-loop single-stranded (ssDNA) accumulation. is an intrinsically disordered interacts with both C-NHEJ complexes in RNA-dependent manner. Strikingly, recruitment factors highly sensitive liquid-liquid phase separation inhibitors, suggestive condensate formation. propose facilitates CSR by forming stabilizing ribonucleoprotein complex preventing excessive accumulation, otherwise would cause persistent aberrant repair, leading genomic instability.
Language: Английский
Citations
18
Trends in Biochemical Sciences, Journal Year: 2020, Volume and Issue: 46(3), P. 184 - 199
Published: Nov. 26, 2020
Mature B cells rely on a multilayered regulatory framework to ensure that S region DSBs are preferentially channeled into the NHEJ pathway.The structure of AID-induced breaks influences both DSB end-processing mode and end-joining pathway choice.Both SSA factor RAD52 A-EJ protein HMCES contribute strand pairing activities during repair DSBs.Repair AID-initiated is influenced by Igh locus-specific organizational features productive events leading CSR. 53BP1 contributes structural resection modulatory roles regulation CSR outcomes.Shieldin CST complexes Rif1 downstream effectors, actively counteract processing ssDNA combining inhibition DNA end limited fill-in synthesis resected tracks. Immunoglobulin (Ig) class switch recombination (CSR) process occurring in mature diversifies effector component antibody responses. initiated activity cell-specific enzyme activation-induced cytidine deaminase (AID), which leads formation programmed double-strand (DSBs) at Ig heavy chain (Igh) locus. use complex reactions CSR, avoid aberrant causing lymphomagenic chromosomal translocations. Here, we review pathways acting their functional interplay, with particular focus latest developments molecular composition mechanistic regulation. Our immune system able generate diverse repertoire antibodies (or Igs, see Glossary) can collectively recognize efficiently dispose an impressive number pathogens. Antibodies produced terminally differentiated lymphocytes known as plasma cells, different routes eliminate These alternative functions specified isotypes classes) [1.Bruhns P. Jönsson F. Mouse human FcR functions.Immunol. Rev. 2015; 268: 25-51Crossref PubMed Scopus (160) Google Scholar]. A lymphocyte it expresses via [2.Chaudhuri J. Alt F.W. Class-switch recombination: interplay transcription, deamination repair.Nat. Immunol. 2004; 4: 541-552Crossref Scholar,3.Pan-Hammarström Q. et al.Class Switch Recombination : Comparison Between Human.Adv. 2007; 93: 1-61Crossref (0) replaces constant portion IgM one (IgG, IgA, or IgE), thus changing function without altering its specificity At level, somatic reaction occurs within locus (Figure 1) The temporary disruption genome integrity entails places crossroads between establishment protective immunity, need maintain stability. inability introduce these responsible for primary deficiencies (CSR immunodeficiencies) [4.de la Morena M.T. Clinical Phenotypes Hyper-IgM Syndromes.J Allergy Clin Immunol Pract. 2016; 1023-1036Abstract Full Text PDF Scholar,5.Durandy A. al.Primary deficiencies.Nat. 2013; 13: 519-533Crossref (126) Conversely, CSR-dependent be substrate translocations, hallmark several cell lymphomas [6.Casellas R. al.Mutations, kataegis translocations cells: understanding AID promiscuous activity.Nat. 16: 164-176Crossref Therefore, isotype diversification fundamental aspect physiology important implications health disease. In view recent COVID-19 pandemic, has brought worldwide attention crucial societal played comprehensive processes contributing humoral responses particularly timely. this review, describe operating DSBs, highlight aspects Since been extensively investigated mice, refer primarily mouse details obtained model system, reference other organisms where appropriate. allele comprises rearranged VDJ exon, eight exon sets encoding (C) regions (referred C genes) [7.Yewdell W.T. Chaudhuri transcriptional serenAID: role noncoding RNAs recombination.Int. 2017; 29: 183-196Crossref (15) Scholar] 1). Except Cδ, each gene preceded constitutively expressed (Cμ region) cytokine-inducible (downstream regions) 5′ intronic promoter, intervening (I) (S) region. highly repetitive stretches extend up 10–12 kb [8.Stavnezer Antibody switching.Adv. 1996; 61: 79-146Crossref They bear repeat units 10–80 bp length G-rich nontemplate Cδ cotranscribed Cμ, IgD expression results from splicing pre-mRNA transcript composed genes. However, noncanonical S-like identified, rare Cμ have reported specific subsets mice humans [9.Chen K. al.Immunoglobulin D enhances surveillance activating antimicrobial, proinflammatory cell-stimulating programs basophils.Nat. 2009; 10: 889-898Crossref (269) Scholar, 10.Rouaud al.Elucidation enigmatic class-switch germline deletion IgH 3' region.J. Exp. Med. 2014; 211: 975-985Crossref 11.Choi J.H. al.IgD switching microbiota mucosa-associated lymphoid tissue mice.Proc. Natl. Acad. Sci. U. S. 114: E1196-E1204Crossref 12.Arpin C. al.The normal counterpart myeloma germinal center displays mutated IgVH gene, Cμ-Cδ switch, λ light expression.J. 1998; 187: 1169-1178Crossref Following activation, introduced donor Sμ acceptor result [13.Feng Y. al.AID diversification: there back again.Trends 2020; 41: 586-600Abstract deaminates cytosine residues uracil single-stranded (ssDNA) exposed transcription (germline transcription; GLT) across recombining S–C Transcription promoter corresponding isotype. U:G mispairs further processed base excision (BER) mismatch (MMR) pathways, generation multiple per [14.Methot S.P. Di Noia J.M. Molecular mechanisms hypermutation recombination.Adv. 133: 37-87Crossref (85) initiates also (SHM), additional During SHM, cytosines variable (Igl) loci. resulting mismatches converted single point mutations potential increase binding affinity molecule towards cognate antigen Because initiating immunity; however, source instability. Although loci represent preferential targets, introduces lesions non-Ig genes throughout (off-targets), many translocation partners hijack ubiquitous damage response sense, transduce, [15.Boboila al.Classical lymphocyte-specific general breaks.in: Advances Immunology. 2012: 1-49Google detected MRE11–RAD50–NBS1 (MRN) complex, activates ataxia telangiectasia-mutated kinase (ATM). ATM main signaling cascade, once activated, phosphorylates plethora factors, including histone variant H2AX. Phosphorylation H2AX (γH2AX) key intermediate step cascade promotes assembly factors over large chromatin surrounding break site. Accordingly, ATM, MRN impaired Mammalian evolved four mechanistically distinct DSBs: nonhomologous joining (NHEJ), (A-EJ), single-strand annealing (SSA), homologous (HR) 2). operate kinetics, mediated differ extent sequence homology used [16.Hustedt N. Durocher D. control cycle.Nat. Cell Biol. 19: 1-9Crossref (245) Scholar,17.Scully al.DNA repair-pathway choice mammalian cells.Nat. Mol. 2019; 20: 698-714Crossref (130) Furthermore, they regulated cell-cycle-dependent manner HR predominantly G2 phases, whereas active G1/S/G2 phases early G1 phase completed late G1/early [18.Schrader C.E. al.Activation-induced deaminase-dependent occur G 1 cycle depend upon repair.J. 179: 6064-6071Crossref 19.Wiedemann E.M. replication origins immunoglobulin regulate R-loop-dependent manner.Cell Rep. 17: 2927-2942Abstract (22) 20.Petersen required initiate Nbs1/γ-H2AX sites switching.Nature. 2001; 414: 660-665Crossref (416) 21.Wang restricts G1.J. 214: 49-58Crossref (24) Scholar], major involved breaks. term microhomology-mediated (MMEJ) sometimes synonym A-EJ. interchangeable two terms might misleading since generates junctions microhomologies. genetically microhomologies anneal ends enable ligation. [22.Chang H.H.Y. al.Non-homologous 18: 495-506Crossref (368) Scholar,23.Pannunzio N.R. al.Nonhomologous breaks.J. Chem. 2018; 293: 10512-10523Abstract (136) repairs broken direct ligation mechanism requires KU70/KU80 (Ku) heterodimer ligase IV (LIG4) cofactor X-ray cross-complementing (XRCC)4 (Box Figure Ku, LIG4, XRCC4 evolutionary conserved considered core components. clean (blunt compatible overhangs) ligation, (incompatible overhangs bearing chemical modifications) intervention enzymes render them Modification context exo- endo-nucleolytic 3′ exposure short typically nucleotides greatly facilitate because terminal allows relatively stable intermediates. nucleolytic Gap-filling necessary ligatable small deletions insertions characteristic junctions.Box 1DSB Repair NHEJNHEJ Ku abundant cellular high ends. As consequence, usually first bind end. blunt lacking microhomology, association XRCC4–LIG4 catalyze either duplex When prerequisite NHEJ, DNA-PKcs nuclease Artemis recruited Ku-bound possesses DNA-PKcs-dependent endonuclease acts double-stranded (dsDNA) transitions hairpins [102.Chang Lieber M.R. Structure-specific Artemis: complex.Nucleic Acids Res. 44: 4991-4997Crossref addition, DNA-PKcs-independent exonuclease ssDNA. act transiently open pseudo-Y structure, resect expose microhomologies, explains why some loss annealing. nucleases may ends, appears majority events.In addition degradation, modified polymerases, Pol X family members POLλ POLμ being polymerases incorporates template-dependent manner, gaps generated long [103.Bebenek al.Structure-function studies polymerase λ.Biochemistry. 53: 2781-2792Crossref facilitates mismatched adding overhang -independent eventually microhomology [104.Moon A.F. al.Sustained site rigidity μ.Nat. Struct. 21: 253-260Crossref (40) Additional accessory proteins, such tyrosyl phosphodiesterase (TDP)1, polynucleotide (PNK), aprataxin participate minor fraction cannot action described previous text XRCC4-like (XLF; Cernunnos) paralog XLF (PAXX) suggested stimulate incompatible stabilizing juxtaposition absence stability conferred Finally, modulator retrovirus infection (MRI; CYREN) was recently identified adaptor promote facilitating recruitment and/or retention [39.Hung P.J. al.MRI classical non-homologous joining.Mol. Cell. 71 (e8): 332-342Abstract (35) Scholar,105.Arnoult al.Regulation inhibitor CYREN.Nature. 549: 548-552Crossref (70) Scholar,106.Slavoff S.A. al.A reading frame (sORF)-Encoded polypeptide stimulates joining.J. 289: 10950-10957Abstract (60) Both PAXX MRI partially overlapping 40.Kumar V. al.PAXX functionally redundant G1-arrested progenitor B-cell line.Proc. 113: 10619-10624Crossref 41.Liu X. KU accumulation essential XLF-deficient mice.Nat. Commun. 8: 1-13Crossref 42.Balmus G. al.Synthetic lethality development.Genes Dev. 30: 2152-2157Crossref (43) events.
Language: Английский
Citations
48
Journal of Molecular Medicine, Journal Year: 2021, Volume and Issue: 100(3), P. 351 - 372
Published: Sept. 4, 2021
Abstract Human sterile α motif and HD domain-containing protein 1 (SAMHD1), originally described as the major cellular deoxyribonucleoside triphosphate triphosphohydrolase (dNTPase) balancing intracellular deoxynucleotide (dNTP) pool, has come recently into focus of cancer research. As outlined in this review, SAMHD1 been reported to be mutated a variety types expression is dysregulated many cancers. Therefore, regarded tumor suppressor certain tumors. Moreover, it proposed that might fulfill requirements driver gene development or promote so-called mutator phenotype. Besides its role dNTPase, several novel functions have light only recently, including negative regulator innate immune responses facilitator DNA end resection during replication repair. can placed at crossroads various processes. The present review summarizes chemotherapy sensitivity, highlights mutations found types, aims discuss functional consequences well underlying mechanisms dysregulation potentially involved development.
Language: Английский
Citations
30
Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)
Published: Nov. 7, 2022
Abstract Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) has a dNTPase-independent function in promoting DNA end resection to facilitate double-strand break (DSB) repair by homologous recombination (HR); however, it is not known if upstream signaling events govern this activity. Here, we show that SAMHD1 deacetylated the SIRT1 sirtuin deacetylase, facilitating its binding with ssDNA at DSBs, promote HR. complexes deacetylates conserved lysine 354 (K354) specifically response DSBs. K354 deacetylation promotes HR but tetramerization or dNTPase Mechanistically, recruitment DSBs which turn facilitates CtIP binding, leading promotion of genome integrity. These findings define mechanism governing stability.
Language: Английский
Citations
21
Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(8), P. 4422 - 4439
Published: April 3, 2024
Abstract Efficient repair of DNA double-strand breaks in the Ig heavy chain gene locus is crucial for B-cell antibody class switch recombination (CSR). The regulatory dynamics pathway direct CSR preferentially through nonhomologous end joining (NHEJ) over alternative (AEJ). Here, we demonstrate that histone acetyl reader BRD2 suppresses AEJ and aberrant as well random genomic sequence capture at junctions. deficiency impairs (S) region synapse, optimal damage response (DDR), increases break resection. Unlike BRD4, a similar bromodomain protein involved NHEJ CSR, loss does not elevate RPA phosphorylation R-loop formation S region. As stabilizes cohesion loader NIPBL regions, or shows comparable deregulation S-S synapsis, DDR, choice during CSR. This finding extends beyond BRD4 have been linked to Cornelia de Lange syndrome, developmental disorder exhibiting defective isotype switching. interplay between these proteins sheds light on intricate mechanisms governing immune system functionality.
Language: Английский
Citations
3
Nucleic Acids Research, Journal Year: 2021, Volume and Issue: 49(5), P. 2598 - 2608
Published: Jan. 19, 2021
Abstract Aberrant end joining of DNA double strand breaks leads to chromosomal rearrangements and insertion nuclear or mitochondrial into breakpoints, which is commonly observed in cancer cells constitutes a major threat genome integrity. However, the mechanisms that are causative for these insertions largely unknown. By monitoring different linear substrates introduced HEK293 cells, as well by examining CRISPR/Cas9 induced HeLa we provide evidence dNTPase activity SAMHD1 impedes aberrant resynthesis at during joining. Hence, expression low intracellular dNTP levels lead shorter repair joints impede distant regions prior repair. Our results reveal novel role new insights how loss may contribute instability development.
Language: Английский
Citations
19
iScience, Journal Year: 2024, Volume and Issue: 27(2), P. 108907 - 108907
Published: Jan. 19, 2024
Report a rigorous SAMHD1 chemical probe discovery pipelineIdentified series of low micromolar inhibitors, exemplified by
Language: Английский
Citations
2
Viruses, Journal Year: 2022, Volume and Issue: 14(8), P. 1622 - 1622
Published: July 26, 2022
Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) has been the primary interest among studies on antiviral discovery, viral replication kinetics, drug resistance, and evolution. Following infection entry into target cells, HIV-1 core disassembles, RT concomitantly converts RNA double-stranded proviral DNA, which is integrated host genome. The successful completion of life cycle highly depends enzymatic DNA polymerase activity RT. Furthermore, long known as an error-prone due to its lack proofreading exonuclease properties. Indeed, low fidelity considered one key factors in uniquely high rate mutagenesis HIV-1, leads efficient escape from immune therapeutic selective pressures. Interestingly, a series kinetics non-dividing myeloid cells specific restriction factor, SAM domain, HD domain-containing protein, SAMHD1, suggest that cell tropism are mechanistically connected. Here, we review not only target, but also potential evolutionary mechanistic crosstalk unique features RT, tropism, genetic mutation, SAMHD1 protein.
Language: Английский
Citations
8
Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown, P. 257 - 308
Published: Jan. 1, 2024
Language: Английский
Citations
1
ACS Infectious Diseases, Journal Year: 2021, Volume and Issue: 7(2), P. 318 - 332
Published: Jan. 8, 2021
The maintenance of deoxyribonucleotide triphosphate (dNTP) homeostasis through synthesis and degradation is critical for accurate genomic mitochondrial DNA replication fidelity. Trypanosoma brucei makes use both the salvage de novo pathways provision pyrimidine dNTPs. In this respect, sterile α motif histidine-aspartate domain-containing protein 1 (SAMHD1) appears to be most relevant dNTPase controlling dNTP/deoxynucleoside in mammalian cells. Here, we have characterized role a unique trypanosomal SAMHD1 orthologue denominated TbHD52. Our results show that TbHD52 enzyme essential bloodstream forms T. brucei. Knockout cells are auxotrophs exhibit strong defects integrity, cell cycle progression, nuclear kinetoplast segregation absence extracellular thymidine. lack can counteracted by overexpression human dCMP deaminase, an directly involved dUMP formation yet absent trypanosomes. Furthermore, cellular dNTP quantification metabolomic analysis null mutants revealed perturbations nucleotide metabolism with substantial accumulation dCTP cytosine-derived metabolites while dTTP was significantly reduced. We propose HD-domain-containing kinetoplastids plays contributes deoxycytidine required biosynthesis.
Language: Английский
Citations
9